rs3793801

Positions:

• chr10-49664866-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020549.5(CHAT):​c.2067C>T​(p.Ile689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,196 control chromosomes in the GnomAD database, including 2,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I689I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (266 hom., cov: 32)
  • Exomes 𝑓: 0.015 (2344 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.22

Genes affected

CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-49664866-C-T is Benign according to our data. Variant chr10-49664866-C-T is described in ClinVar as [Benign]. Clinvar id is 128722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49664866-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.2067C>T	p.Ile689=	synonymous_variant	15/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.2067C>T	p.Ile689=	synonymous_variant	15/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2344 AN: 152188 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0325 AC: 8179 AN: 251496 Hom.: 893 AF XY: 0.0328 AC XY: 4462 AN XY: 135922

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.307

Gnomad SAS exome AF: 0.0557

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0145 AC: 21210 AN: 1461890 Hom.: 2344 Cov.: 32 AF XY: 0.0155 AC XY: 11298 AN XY: 727248

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00892

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.0529

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0154 AC: 2339 AN: 152306 Hom.: 266 Cov.: 32 AF XY: 0.0182 AC XY: 1357 AN XY: 74466

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.0582

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00703 Hom.: 194

Bravo AF: 0.0150

Asia WGS AF: 0.149 AC: 516 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3793801; hg19: chr10-50872912; COSMIC: COSV60321243;